Phase IIA Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid With or Without Aspirin, for HIV-associated Tuberculous Meningitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 4
- 主要终点
- Number of participants in each arm who develop treatment related adverse events (AEs).
研究概览
简要总结
LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). The study will recruit 100 HIV-infected adults with TBM across four sites in South Africa.
The primary endpoint is the occurrence of solicited treatment-related adverse events.
Secondary endpoints include death and disability (including neurocognitive impairment), radiological outcomes, and the occurrence of immune reconstitution inflammatory syndrome (IRIS).
A nested pharmacokinetic (PK) substudy aims to:
- Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF.
- Evaluate the relationship between drug exposures, toxicity and efficacy.
- Compare exposures between intravenous and oral RIF administration.
- Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).
详细描述
HIV-1 infected adults with newly-diagnosed TBM (n = 100) will be recruited from four public-sector hospitals in Cape Town and Port Elizebeth, South Africa. Participants will be randomised across two experimental (n = 30 each) and one standard of care (n = 40) arms. Treatment will be provided in all arms for 56 days, after which participants will be referred back to public sector facilities to complete standard therapy for HIV-associated TBM.
The primary objective of the study is to investigate the safety of enhanced antimicrobial therapy including increased dose RIF and LZD with or without adjunctive aspirin added to standard therapy for TBM in HIV-1 infected adults.
Secondary objectives are;
- To determine cerebrospinal fluid M.tb culture positivity and Gene Xpert® Ultra positivity at baseline and at 3 and 28 days post treatment by allocation.
- To evaluate the effect of aspirin and enhanced tuberculosis treatment on the incidence of immune reconstitution syndrome in participants starting antiretroviral therapy.
- To evaluate the effect of high dose rifampicin and linezolid, with and without aspirin on the transcriptional signature derived from whole blood and cerebrospinal fluid RNA sequencing, as well as the metabolomic and proteomic profiles, in tuberculous meningitis.
- To evaluate the effect of high dose rifampicin and linezolid with and without aspirin on central nervous system imaging in conjunction with clinical, immunological and transcriptional profiling.
- To store biological samples for future analysis of potential biomarkers of treatment efficacy and/or novel diagnostic assays.
- To determine i) whether host genotype, including LTA4H genotype, influences therapeutic effect of aspirin in HIV-TBM and ii) the pharmacogenetic influence on rifampicin and linezolid exposures and toxicity.
All participants will receive antitubercular chemotherapy and corticosteroids as standard of care as per national South African guidelines. Participants allocated to experimental arms 2 and 3 will receive additional rifampicin (total oral dose 35 mg/kg/day) plus oral linezolid 1200mg daily for the first 28 days, reduced to 600 mg daily for the next 28 days. Those randomized to experimental arm 3 will also receive oral aspirin 1000 mg daily.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 seropositivity by rapid test, confirmed by enzyme-linked immunosorbent assay (regardless of Antiretroviral Therapy (ART) status);
- •Age 18 years or older;
- •Tuberculous meningitis defined as 'possible', 'probable' or 'definite' as per published case definitions
排除标准
- •Rifampicin-resistant M. tb detected in any microbiological specimen;
- •History of allergy or hypersensitivity to H, E, R and Z, LZD or ASA;
- •Received more than 5 days of antitubercular therapy in the 30 days prior to screening;
- •Received a dose of ASA or any other NSAID within 2 weeks of screening;
- •CSF unobtainable by lumbar puncture or another procedure;
- •Evidence of bacterial or cryptococcal meningitis;
- •Severe concurrent uncontrolled opportunistic infection including but not limited to active cytomegalovirus-associated disease, Kaposi sarcoma, Pneumocystis jirovecii pneumonia, HIV related or unrelated malignancy or gastrointestinal bleeding;
- •Any other form of immunosuppressive therapy including antineoplastic and biologic agents apart from corticosteroids;
- •Is pregnant in the third trimester;
- •Peripheral neuropathy scoring Grade 3 or above on Brief Peripheral Neuropathy Score
- •Any disease or condition in which the use of the standard TB drugs or any of their components is contraindicated, including but not limited to allergy to any TB drug or their components;
- •The presence of one or more of the following:
- •Estimated glomerular filtration rate (eGFR) < 20ml/min/1.73m2 (using the Cockcroft-Gault equation)
- •International normalised ration (INR) > 1.4 and/or clinical evidence of liver failure or decompensated cirrhosis
- •Hemoglobin < 8.0 g/dL
- •Platelets < 50 x109 /L
- •Neutrophils < 0.5 x 109 cells/L;
- •The patient has any disease or condition in which any of the medicinal products listed in the section pertaining to prohibited medication is used and cannot be safely stopped;
- •The patient has a known or suspected, current or history of drug abuse, within the past 2 years, that is, in the opinion of the investigators, sufficient to compromise the safety or cooperation of the patient.
研究组 & 干预措施
Standard of care anti-tubercular therapy
Standard of care anti-TB treatment. (10 mg/kg oral rifampicin, 5 mg/kg oral isoniazid, 15 mg/kg oral ethambutol and 25 mg/kg oral pyrazinamide daily for 2 months as fixed dose combination tablets (followed by 10 mg/kg oral rifampicin and 5 mg/kg isoniazid daily for 4-7 months in routine care after study completed)).
干预措施: Standard of Care anti-tuberculous therapy (Drug)
Standard of care anti-tubercular therapy
Standard of care anti-TB treatment. (10 mg/kg oral rifampicin, 5 mg/kg oral isoniazid, 15 mg/kg oral ethambutol and 25 mg/kg oral pyrazinamide daily for 2 months as fixed dose combination tablets (followed by 10 mg/kg oral rifampicin and 5 mg/kg isoniazid daily for 4-7 months in routine care after study completed)).
干预措施: Dexamethasone (Drug)
Intensified anti-tubercular therapy
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days).
干预措施: Linezolid (Drug)
Intensified anti-tubercular therapy
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days).
干预措施: High dose rifampicin (Drug)
Intensified anti-tubercular therapy
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days).
干预措施: Standard of Care anti-tuberculous therapy (Drug)
Intensified anti-tubercular therapy
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days).
干预措施: Dexamethasone (Drug)
Intensified anti-tubercular therapy plus aspirin
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)
干预措施: Linezolid (Drug)
Intensified anti-tubercular therapy plus aspirin
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)
干预措施: High dose rifampicin (Drug)
Intensified anti-tubercular therapy plus aspirin
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)
干预措施: Aspirin (Drug)
Intensified anti-tubercular therapy plus aspirin
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)
干预措施: Standard of Care anti-tuberculous therapy (Drug)
Intensified anti-tubercular therapy plus aspirin
Standard of care anti-TB therapy as described in Arm 1,
Plus additional 25 mg/kg rifampicin (total dose rifampicin 35 mg/kg orally for the first 56 days of treatment) and linezolid ( 1,200 mg orally daily for first 28 days reduced to 600 mg daily for next 28 days),
Plus aspirin (1000mg orally daily for the first 56 days of Tuberculous Meningitis treatment)
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Number of participants in each arm who develop treatment related adverse events (AEs).
时间窗: 56 days
The amount of participants who develop any of the following treatment related adverse events by the time they have been on treatment for 56 days will be counted: Peripheral neuropathy, optic neuropathy, anaemia, neutropaenia, thrombocytopaenia, upper gastro-intestinal haemorrhage, intracerebral haemorrhage, drug-induced liver injury.
次要结局
- Death and disability after 56 days on treatment.(56 days)
- Death at day 56 and day 180.(180 days)
- Number of participants who develop Grade 3 or Grade 4 adverse events (AEs).(56 days)
- Number of participants in whom experimental drugs had to be stopped.(56 days)
- Linezolid toxicity(56 days)
- Major bleeding events.(180 days)
- Cerebrospinal fluid culture conversion.(Day 28 and day 56)
- The occurrence of TBM-immune reconstitution inflammatory syndrome(56 days)
- Changes on brain imaging(Day 56)
- Number of participants who are disabled.(180 days)
研究者
Robert J Wilkinson
National Principal Investigator
University of Cape Town